1. FIELD OF THE INVENTION
The present invention relates to methods of preventing graft rejection following solid organ transplantation. More specifically, the invention relates to a method of preventing graft rejection in solid organ transplantation, by administering succinylacetone to recipients of solid organ transplants.
2. DESCRIPTION OF RELATED ART
Succinylacetone (4,6-dioxoheptanoic acid) is an irreversible inhibitor of the second enzyme of the heme biosynthetic pathway, delta-amino levulinic acid dehydrase (ALAD). Initial studies with the compound focused on its ability to inhibit the growth of erythroleukemic cells, through inhibition of heme biosynthesis, but it is also capable of impairing the growth of other tumors by a mechanism independent of heme biosynthesis. Such an activity is disclosed in the article, Tschudy et al, "Growth Inhibitory Activity of Succinylacetones: Studies with Walker 256 Carcinosarcoma" Oncology 40:148 (1983), which is hereby incorporated by reference. Notwithstanding succinylacetone's ability to initially inhibit the growth of the Walker 256 tumor, continuous treatment with succinylacetone can actually facilitate allogeneic tumor growth in rats by suppressing the normal immune rejection process.
Succinylacetone is also active in suppressing rat antibody responses to sheep red blood cells in vivo and in inhibiting mitogen and antigen responses by human lymphocytes in vitro. This characteristic of the compound is disclosed in Tschudy et al, "Immuno-suppressive Activity of Succinylacetone" J. Lab & Clin. Med., 99(4):526 (1982), hereby incorporated by reference.
In spite of the potent effects associated with the administration of succinylacetone, one month's treatment with the compound has been shown not to demonstrate significant histopathologic abnormalities in any non-lymphoid organ. Furthermore, there was a 12% decrease in hematocrit and a 20% decrease in hemoglobin with such administration, due to suppression of heme production, this decrease in hemoglobin is only 40% of what would be expected if there had been total inhibition of heme production, ibid.
Succinylacetone has also been successfully used to totally inhibit graft vs host disease (GVHD) in allogeneic bone marrow transplantation. For example, Journal of Immunology, 139(9), 2845-2849(1987), disclose succinylacetone to be effective in preventing graft vs host disease, where it is shown that in spite of succinylacetone's strong effects on heme biosynthesis and immune function, succinylacetone does not interfere with engraftment in hematopoietic reconstitution. Furthermore, after one month of treatment, there was only a minor depression of hemoglobin and lymphocytes in the blood and these parameters normalized when the drug was stopped. Further, animals treated with succinylacetone gained weight and no toxicity to other organ systems was seen.
U.S. Pat. No. 4,670,467, issued to Hess et al, hereby incorporated by reference, also discloses a method of controlling graft versus host reaction with succinylacetone.
The effects of succinylacetone on the development of S-antigen-induced experimental autoimmune uveitis (EAU) in rats has been studied and in vivo treatment with succinylacetone has been shown to inhibit in vitro S-antigen-induced lymphocyte proliferative responses in cells from popliteal lymph nodes, as well as decrease S-antigen antibody production, Skolic et al, Clinical Immunology and Immunopathology, 49, 63-71 (1988).
Furthermore, U.S. Pat. application Ser. No. 07/191,067 filed on May 6, 1988, hereby incorporated by reference, is directed to a method of treating autoimmune disease using succinylacetone.
Of the above references, none do any more than simply conjecture that it might be possible to use succinylacetone in solid organ transplantation.